Significance: We demonstrate that intracellular Ca ²⁺ leak causes mitochondrial Ca ²⁺ overload and dysfunction in postischemic heart failure (HF). In particular, sarcoplasmic reticulum (SR) Ca ²⁺ leak via type 2 ryanodine receptor (RyR2)—but not type 2 inositol 1,4,5-trisphosphate receptor (IP3R2)—channels plays a fundamental role in the pathophysiology of mitochondrial Ca ²⁺ overload and dysfunction in HF. We present here a previously undisclosed molecular mechanism in HF with crucial implications in cardiac physiology. Indeed, our data establish a feedback loop between SR and mitochondria in which SR Ca ²⁺ leak triggers mitochondrial dysfunction and increases the production of free radicals, which in turn lead to posttranslational modifications of RyR2 and enhance intracellular Ca ²⁺ leak, thereby contributing to impaired cardiac function after myocardial infarction.

The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations.

Angiopoietin-like proteins (ANGPTLs) are a family of proteins structurally similar to the angiopoietins. To date eight ANGPTLs have been discovered, named ANGPLT1 to ANGPLT8. Emerging evidence implied a key role for ANGPTLs in the regulation of a plethora of physiological and pathophysiological processes. Most of ANGPTLs exhibit multibiological properties, including established functional roles in lipid and glucose metabolism, inflammation, hematopoiesis and cancer. This report represents a systematic and updated appraisal of this class of proteins, focusing on the main features of each ANGPLT.

Oxidative stress has been suggested to play a role in the pathogenesis of atrial fibrillation (AF). Indeed, the prevalence of AF increases with age as does oxidative stress. However, the mechanisms linking redox state to AF are not well understood. In this study we identify a link between oxidative stress and aberrant intracellular Ca²⁺ release via the type 2 ryanodine receptor (RyR2) that promotes AF. We show that RyR2 are oxidized in the atria of patients with chronic AF compared with individuals in sinus rhythm. To dissect the molecular mechanism linking RyR2 oxidation to AF we used two murine models harboring RyR2 mutations that cause intracellular Ca²⁺ leak. Mice with intracellular Ca²⁺ leak exhibited increased atrial RyR2 oxidation, mitochondrial dysfunction, reactive oxygen species (ROS) production and AF susceptibility. Both genetic inhibition of mitochondrial ROS production and pharmacological treatment of RyR2 leakage prevented AF. Collectively, our results indicate that alterations of RyR2 and mitochondrial ROS generation form a vicious cycle in the development of AF. Targeting this previously unrecognized mechanism could be useful in developing effective interventions to prevent and treat AF.

Arginine (L-arginine), is an amino acid involved in a number of biological processes, including the biosynthesis of proteins, host immune response, urea cycle, and nitric oxide production. In this systematic review, we focus on the functional role of arginine in the regulation of endothelial function and vascular tone. Both clinical and preclinical studies are examined, analyzing the effects of arginine supplementation in hypertension, ischemic heart disease, aging, peripheral artery disease, and diabetes mellitus.